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Biomedical subjects

R J Roman

Publications and source records attributed to R J Roman.

At least 181 records · Page 10Linked to original sources
PubMed1981

Meclofenamate and urine concentration with and without exposure of the renal papilla.

The recent finding that inhibitors of prostaglandin synthesis prevent the fall in urine concentration produced by papillary exposure challenges the hypothesis that contact between the pelvic urine and papilla is essential to the renal concentrating process. The present study examines the change in urine osmolality produced by exposure of the renal papilla in rats given meclofenamate. In control animals urine osmolality(Uosmol) decreased 57% after 2 h of exposure of the renal papilla. In rats given meclofenamate 4 mg/kg urine osmolality increased 16%, urine flow decreased 30%, and glomerular filtration rate was unchanged in the nonexposed kidney. Meclofenamate, however, did not alter the decrease in Uosmol seen in the kidney with the exposed papilla. Meclofenamate 10 mg/kg was also ineffective in preventing the fall in urine osmolality produced by papillary exposure, although this higher dose decreased glomerular filtration rate and arterial blood pressure. These results are consistent with the finding that pelvic urine urea is important to the urinary concentrating process and with the hypothesis that urine osmolality falls after papillary exposure because contact between pelvic urine and papilla is interrupted.

Animals↗
PubMed1981

Prostaglandin E2 and F2 alpha reduces urea reabsorption from the rat collecting duct.

The present study examines the possibility that prostaglandins affect the renal tubular handling of urea. Meclofenamate (1 mg.kg-1.h-1), an inhibitor of prostaglandin synthesis, decreased fractional urea clearance from 86 to 67%, increased urine osmolality, and decreased the fractional excretion of water in rats undergoing a hypertonic sodium chloride diuresis. The percentage of [14C]urea microinjected into distal convoluted tubules that was recovered in urine fell from 75 to 64% (P less than 0.01) after meclofenamate. The fraction of injected urea excreted like inulin (direct recovery) was reduced from 20 to 8% (P less than 0.0001) by meclofenamate. Addition of PGE2 (1.2 or 89 pmol) or PGF2 alpha (1.4 pmol) to the microinjectate returned the urinary recovery of the microinjected [14C]urea to the control level, but PGA2 (3 pmol) did not. Direct urea recovery was doubled by PGE2 or PGF2 alpha. These results indicate that prostaglandin E2 and F2 alpha inhibit the reabsorption of urea in the collecting duct. Prostaglandins may participate in the renal concentrating mechanism by altering the inner medullary influx of urea.

Absorption↗
PubMed1981

Sodium orthovanadate diuresis in rats.

The renal actions of differing doses of sodium orthovanadate were studied in conscious and anesthetized female Wistar rats. In conscious rats, sodium orthovanadate was given by i.v. or i.p. injections or by mouth. The most pronounced renal effects were seen after a 5 mg/kg i.p. injection of sodium orthovanadate. Urine flow and sodium excretion increased approximately 400% and urine osmolality fell from 1108 to 549 mOsmol/kg . H2O. Higher doses of sodium orthovanadate (20, 30 and 50 mg/kg) injected i.p. did not cause diuresis and were toxic. In anesthetized rats undergoing a 0.9% NaCl diuresis, i.v. infusion of sodium orthovanadate at a dose of 5 mg/kg/hr significantly increased urine flow and the excretion of sodium, calcium, phosphorus, sulfur, magnesium and chlorine, whereas glomerular filtration rate was unaltered. In anesthetized rats undergoing a water diuresis, i.v. infusion of sodium orthovanadate (5 mg/kg/hr) markedly reduced free-water clearance, indicating that this compound inhibits tubular reabsorption of sodium and chloride in diluting nephron segments. Blood and renal tissue levels of vanadium, measured using emission spectrographic analysis, in rats infused with sodium orthovanadate were 4 times higher than the concentration of sodium orthovanadate (1--10 microM) needed to inhibit 50% of the Na-K-adenosine triphosphate activity of rat renal homogenates in vitro. These data suggest that sodium orthovanadate produces diuresis at least in part by inhibiting Na-K-adenosine triphosphatase and solute transport in the distal nephron, likely the ascending limb of the loop of Henle.

Administration, Oral↗
PubMed1980

Effect of urea concentration of pelvic fluid on renal concentrating ability.

The role of the pelvic urine in the renal concentration process was examined in anesthetized antidiuretic rats. The left ureter was cannulated with perfusion and collection catheters so that the composition of the fluid bathing the papilla could be altered by superperfusing solution of known composition without opening the renal pelvis, exposing the papilla, or altering intrapelvic pressure. The effect on urinary osmotic pressure (Uosmol) of papillary superperfusion with solutions of varying urea concentrations and total osmolality was examined. Papillary superperfusion with solutions containing no urea or less urea than preperfusion pelvic urine caused marked reductions in Uosmol regardless of the osmotic pressure of the solution. Superperfusion solutions with urea concentrations similar to that of preperfusion pelvic urine but lower in osmotic pressure than preperfusion urine produced no change in Uosmol. Superperfusion solutions with urea concentrations higher than that of preperfusion urine and with osmotic pressure equal to that of the preperfusion urine increased Uosmol. Finally, superperfusion of the papilla with urea solutions of greater than 2,370 mosmol/kg H2O and hypertonic to preperfusion urine decreased Uosmol. We conclude that the urea concentration of the pelvic urine plays an essential role in the urinary concentration mechanism.

Animals↗
PubMed1977

Renal tubular site of action of fluoride in Fischer 344 rats.

Methoxyflurane is capable of producing high-output renal failure in some patients and animal models, probably through metabolic liberation of free fluoride. The tubular site of action of fluoride was examined in Fischer 344 rats using clearance techniques. Free water reabsorption (TCH2O) and free water excretion (CH2O) were measured during mannitol or water diuresis in control rats and in rats given methoxyflurane or pretreated with sodium fluoride. Pretreatment produced statistically significant increases in urinary flow (from 10.5 +/- 1.4 to 20.1 +/- 1.9 mul/min/100 g b. wt.), in glomerular filtration rate (from 814 +/- 31 to 1,039 +/- 53 mul/min/100 g b. wt.), in per cent sodium excretion (from 0.107 +/- 0.008 to 0.155 +/- 0.015 per cent), and in per cent water excretion (from 1.27 +/- 0.15 to 2.00 +/- 0.20 per cent). Free water excretion remained relatively unaltered in rats pretreated with fluoride, perhaps due to elevated glomerular filtration rate and/or reduced proximal tubular reabsorption combined with inhibition of reabsorption in the ascending loop. Percentage free water reabsorption, on the other hand, was markedly reduced by the pretreatment, from 2.66 +/- 0.21 to 0.66 +/- 0.09 per cent. The observations are consistent with the hypothesis that fluoride inhibits tubular reabsorption primarily in the medullary portion of the ascending limb of Henle's loop, perhaps by inhibition of an active chloride pump located in this nephron segment.

Animals↗
PubMed1976

Renal tubular transport of 3H-digoxin in saline diuresis in rats.

We evaluated urinary excretion and tubular transport of 3H-digoxin by three different methods in anesthetized rats made diuretic by infusion of 2.5% saline. In one group small volumes of 3H-digoxin and 14C-inulin were injected simultaneously into surface proximal convolutions, and urine was collected serially from both ureters. Digoxin recovery was lower after early (62.1 +/- 5.3%) than after late (86.9 +/- 7.7%) proximal administration but inulin recovery was complete (99.6 +/- 2.7%) after all injections. Most of the digoxin was excreted simultaneously with inulin. Delayed recovery was low. In another group of rats digoxin and inulin were applied directly to the capsule of the left kidney. Two-thirds of the recovered digoxin appeared from the left ureter and one-third from the right. The difference (41.9 +/- 7.4%) is an estimate of transtubular digoxin influx. Digoxin excretion preceded inulin only on the left. Digoxin to inulin concentration ratios were 6 times higher from the left than the right, whereas inulin recoveries from the two sides were similar. In a third group of rats tubular fluid was collected from surface convolutions of proximal and distal tubule. In the accessible segment of the proximal tubule 35.9% of the filtered digoxin was reabsorbed. In the more distal nephron, drug was added into the lumen; this resulted in a net urinary excretion of 80.2 +/- 18.2%. These findings are compatible with free filtration of digoxin at the glomerulus followed by passive proximal tubular reabsorption and an influx against a concentration gradient in the distal nephron.

Animals↗
PubMedDate not supplied

Relative contributions of cyclooxygenase- and cytochrome P450 omega-hydroxylase-dependent pathways to hypoxic dilation of skeletal muscle resistance arteries.

This study determined the contribution of prostanoids, cytochrome P450 (CP450) 4A enzyme metabolites of arachidonic acid, and other potential mediators of hypoxic dilation of isolated rat skeletal muscle resistance arteries. Gracilis arteries (GA) were viewed via television microscopy and dilator responses to hypoxia (reduction in superfusate and perfusate PO2 from approximately 145 to approximately 40 mm Hg) were measured with a video micrometer. Hypoxic dilation of gracilis arteries was severely impaired by either endothelium removal or cyclooxygenase inhibition with indomethacin, but not by nitric oxide synthase inhibition with L-NAME. Treatment of GA with 17-octadecynoic acid (17-ODYA) alone to inhibit CP450 4A enzymes significantly reduced hypoxic dilation from control levels. Treatment of vessels with N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (MS-PPOH) to inhibit the production of epoxyeicosatrienoic acids (EETs) did not alter hypoxic dilation, although treatment with dibromo-dodecenyl-methylsulfimide (DDMS) to inhibit 20-hydroxyeicosatetraenoic acid (20-HETE) production had similar effects as 17-ODYA. Treatment of GA with 6(Z),15(Z)-20-HEDE, a competitive antagonist of the actions of 20-HETE, mimicked the effects of 17-ODYA and DDMS treatment on hypoxic dilation. These results suggest that hypoxic dilation of skeletal muscle resistance arteries primarily represents the effects of enhanced prostanoid release from vascular endothelium, although a contribution of reduced 20-HETE production via CP450 omega-hydroxylase enzymes also regulates hypoxic dilation of these vessels.

Animals↗
PubMedDate not supplied

Role of cytochrome P-450 in elevating renal vascular tone in spontaneously hypertensive rats.

The contribution of cytochrome P-450 metabolites of arachidonic acid in elevating vascular tone in the kidneys of adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was examined using a juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. At 80 mm Hg, the basal internal diameters of arcuate and interlobular arteries and proximal and distal afferent arterioles of the SHR averaged 341 +/- 15.81 +/- 5.24 +/- 0.5 and 19 +/- 0.3 micron, respectively. These diameters were 5-29% smaller (p < 0.05) than those measured in corresponding vessels in WKY rats. Addition of the P-450 inhibitors, ketoconazole (100 microM) or 17-octadecynoic acid (17-ODYA, 20 microM), to the perfusate and bath increased the diameters of the preglomerular vasculature of the SHR by 6-29%, but by only 3-13% in WKY rats and reduced significantly the differences in pressure-diameter relations between the two groups. The rate of formation of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical microsomes was similar in SHR and WKY rats. However, the production of epoxyeicosatrienoic acids (EETs) by cortical microsomes was 87% lower and dihydroxyeicosatrienoic acids (DHETs) 70% higher in the SHR than WKY rats. Ketoconazole (100 microM) reduced the formation of 20-HETE by 80%, and EETs and DHETs production by more than 98% in SHR and WKY rats. 17-ODYA (20 microM) reduced the formation of 20-HETE, EETs and DHETs by more than 98% in both groups. These results suggest that cytochrome P-450 metabolites of arachidonic acid contribute to the elevated renal vascular tone in adult SHR. This may be due to an enhanced vascular responsiveness to vasoconstrictor P-450 metabolites in SHR or an elevated local production of vasoconstrictor eicosanoids in the renal vasculature of SHR rather than in renal cortical tissue.

Animals↗
PubMedDate not supplied

Role of cytochrome P-450 enzymes and metabolites of arachidonic acid in the control of vascular tone.

The metabolism of arachidonic acid (AA) into vasoactive products by cyclooxygenase and lipoxygenase enzymes has been well described, as has their biological relevance. Recently, a number of studies have demonstrated the ability of cytochrome P-450 (P450) enzymes to metabolize AA into biologically important regulators of vascular tone. There are two categories of vasoactive P450 metabolites, namely those catalyzed by epoxygenase enzymes which generate epoxyeicosatrienoic acids (EETs) and those enzymes which generate hydroxyeicosatetraenoic acids (HETEs). Except for 20-HETE, P450 metabolites of AA occur as stereo- and regioisomers which determine, to some extent, their biological activity. 5,6-, 8,9-, 11,12- and 14,15-EETs are generally potent dilators in a number of vascular beds with a sensitivity which appears to increase as the vasculature decreases in size toward capillaries. HETEs, such as 12R- and 20-HETE, can be potent activators of vascular tissue with 20-HETE contracting cerebral and renal microvessels at concentrations of < 10(-10) M. Both EETs and HETEs can be made by vascular and extravascular tissue. Available data suggests that EETs are formed by endothelial and parenchymal tissue while HETEs can be endogenously formed in arterial muscle where they appear to act as second messengers. This review will discuss the molecular biology, stereochemistry, biological activity and importance of P450 metabolites of AA as para- and autocrine controllers of organ blood flow. We will also discuss the large diversity of P450 enzyme isoforms and how such diversity can provide for precise physiological control of vascular tone.

Animals↗
PubMedDate not supplied

Cytochrome P450 metabolites of arachidonic acid as intracellular signaling molecules in vascular tissue.

Recent studies from our laboratory have indicated that vascular smooth muscle cells (VSMC) metabolize arachidonic acid via a P4504A-dependent pathway to 20-hydroxyeicosatetraenoic acid (20-HETE), and that this system serves as a novel signal transduction pathway that plays a central role in the regulation of vascular tone. The major metabolite of arachidonic acid formed in cerebral and renal arteries is 20-HETE. The mRNA and protein for P4504A enzymes, which produce 20-HETE, have been localized in VSMC. 20-HETE is a potent vasoconstrictor, that acts in part by inhibition of the opening of the large conductance, calcium-activated potassium channel, and depolarizes VSMC membrane. A preliminary study also indicated that 20-HETE activates the L-type calcium current in cerebral arterial smooth muscle. Inhibition of the endogenous production of 20-HETE in renal and cerebral arterioles attenuates pressure-dependent myogenic tone in vitro, as well as autoregulation of renal and cerebral blood flow in vivo. There is also evidence that indicates that nitric oxide regulates the formation of 20-HETE by binding and inactivating the P450 heme moiety, thus providing a negative feedback control mechanism for this system. The data outlined suggest that 20-HETE could act as a intracellular second messenger that plays an integral role in the signal transduction processes underlying the development of pressure-dependent myogenic tone.

Animals↗
PubMedDate not supplied

Reversal of delayed vasospasm by TS-011 in the dual hemorrhage dog model of subarachnoid hemorrhage.

PURPOSE: Arachidonic acid is avidly metabolized to a potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid (20-HETE), in the cerebral circulation. 20-HETE has been reported to contribute to the acute fall in cerebral blood flow following subarachnoid hemorrhage (SAH), but its role in the development of delayed vasospasm is unknown. The present study examined whether delayed vasospasm is associated with elevations in 20-HETE in CSF in the dual hemorrhage model of SAH in dogs and if blockade of the synthesis of 20-HETE with N-(3-chloro-4-morpholin-4-yl)phenyl-N'-hydroxyimido formamide (TS-011) can reverse delayed vasospasm in this model. MATERIALS AND METHODS: Delayed vasospasm was induced in 22 adult beagle dogs by dual injection of blood (0.5 mL/kg) into the cisterna magna on days 1 and 4. Sequential samples of CSF were collected before intracisternal injections of blood on days 1 and 4 and after the development of delayed vasospasm on day 7. Sequential angiograms were obtained before and after intracisternal injection of blood on days 1 and 4 and before and 1 hour after administration of TS-011 (1 mg/kg IV) on day 7. RESULTS: The dogs consistently developed delayed vasospasm, and the diameter of the basilar artery fell to 68 +/- 3% (n = 15), 3 days after the second intracisternal injection of blood. The levels of 20-HETE in CSF increased from 4 +/- 2 to 39 +/- 16 pg/mL. In 9 dogs with delayed vasospasm, acute blockade of the synthesis of 20-HETE with TS011 (1 mg/kg IV) significantly increased the diameter of the basilar artery by 39%. Chronic administration of TS-011 (1 mg/kg per day) attenuated the development of delayed vasospasm, and the diameter of the basilar artery fell by 17 +/- 1% versus the 33 +/- 3% decrease in diameter seen in control animals 3 days following the second injection of blood into the cisterna magna. CONCLUSIONS: These results indicate that the development of delayed vasospasm in dogs is associated with an increase in 20-HETE levels in CSF, and acute blockade of the synthesis of 20-HETE with TS-011 reverses delayed vasospasm in this model.

Animals↗